Biography: Born in Sheffield, Alabama, Thompson grew up attending the public schools in Lawrenceburg, Tennessee. He attended Memphis State University where he earned an undergraduate degree in philosophy and political science in 1964. He received a J.D. degree from Vanderbilt University in 1967. He was admitted to the Tennessee bar in 1967 and commenced the practice of law, serving as an assistant U.S. attorney from 1969-1972. He was the campaign manager for Senator Howard Baker's successful re-election campaign in 1972, which led to a close personal friendship with Baker, and from 1973-1974, he served as co-chief counsel to the Senate Watergate Committee in its investigation of the Watergate scandal. He was responsible for Baker's asking one of the questions that is said to have led directly to the downfall of President Richard Nixon – "What did the President know, and when did he know it?"

In 1977, Thompson took on a Tennessee Parole Board case that ultimately toppled Tennessee Governor Ray Blanton from power on charges of selling pardons. The scandal became the subject of a book and a movie titled Marie (1985) in which Thompson played himself, supposedly because the producers were unable to find a professional actor who could play him plausibly. This film launched his acting career. Thompson would go on to appear in numerous motion pictures, including The Hunt for Red October (1990), Cape Fear (1991) and In the Line of Fire (1993). Thompson's roles are generally portrayals of characters who are very similar to his real life persona, much in the tradition of performers such as John Wayne.

On November 8, 1994, Thompson was elected to the United States Senate to fill the unexpired portion of the term ending January 3, 1997, left vacant by the resignation of Al Gore, defeating six-term Democratic U.S. Representative Jim Cooper in a landslide which represented the most votes anyone had ever received for a statewide office in Tennessee history up to that point. Thompson took the oath of office on December 2, 1994. Almost immediately upon his arrival in Washington, D.C. ("while I was still unpacking my boxes," as he put it) Thompson was selected by the Republicans to give a reply to a nationally-televised address by President Bill Clinton. This was no doubt due to his acting background, but many pundits saw this as an attempt to groom him for an even larger political role. Thompson was easily re-elected in 1996 for the term ending January 3, 2003 over Democratic attorney Houston Gordon of Ripley, Tennessee by an even larger margin than that by which he had defeated Cooper two years earlier. While in the Senate, he was chair of the Committee on Governmental Affairs from 1997 to January 3, 2001 and January 20, 2001 to June 6, 2001, when the reorganization of the Senate prompted by the resignation of James Jeffords of Vermont from the Republican Party changed the control of the Senate. Thompson then became the ranking minority member.

Thompson was not a candidate for re-election in 2002. He had never planned to make a lifetime career of the Senate, and had often publicly stated as much. Although he announced in the wake of the September 11, 2001 attacks his intention to seek re-election, upon further reflection, which seems to have been prompted in large part by the sudden death of his daughter, he decided not to pursue this course. In the final months of his term, he joined the cast of the long-running NBC television series Law & Order, playing the character of District Attorney Arthur Branch. In doing so, he became the first serving U.S. Senator also to take a full-time television acting job; however, his first scenes as Branch were filmed during the Senate's August 2002 recess, so he missed no legislative time in order to act on television. He is reportedly paid $100,000 per episode of the show in which he appears; if this is in fact true, he earns more from appearing in two shows than he did in an entire year as a Senator, and will earn nearly twice in one television season what his earnings were for his entire Senate career. In the spring of 2005 Thompson concurrently played the role on both the original series and short-lived sister series Law & Order: Trial by Jury. He is one of very few actors who played the same regular character on two different series simultaneously.